PROJECT SUMMARY/ABSTRACT Cognitive behavioral therapies (CBT), a first line treatment for posttraumatic stress disorder (PTSD), have limitations particularly in treating hyperarousal symptoms. It is, therefore, imperative to identify strategies to improve effectiveness of treatments for PTSD. Disturbed sleep is common in PTSD. Sleep has been implicated in learning processes that are a key to adaptive processing of trauma memories. Findings of our preliminary study of people with PTSD suggest that sleep characteristics indicating increased nocturnal arousal compromise therapeutic effects of written narrative exposure (WNE) intervention (writing about one?s traumatic experience). Orexins (hypocretins) are neuropeptides implicated in regulating both sleep/wake and stress responses and emotional behaviors. A dual orexin receptor antagonist, suvorexant, has been found to enhance sleep characteristics associated with emotional adaptation in humans. Administration of an orexin receptor-1 antagonist to mice facilitated extinction of conditioned fear, an animal model of recovery from PTSD and anxiety disorders. The long-term objectives of the candidate?s research program are to elucidate neurophysiological mechanisms underlying the potential for sleep to contribute to resilience and PTSD recovery and apply this knowledge to improve PTSD prevention and treatment. To accomplish these objectives, the following specific aims will be pursued: 1) to examine effects of pharmacologically blocking the orexin system after WNE on sleep, PTSD symptoms, and intersession habituation; and 2) to use an animal model to elucidate neural mechanisms underlying the effects of inhibiting the orexin system on sleep and memory consolidation following fear extinction. In the proposed clinical project, adult participants with PTSD will complete WNE in the evening and morning with intervening sleep, and either suvorexant (FDA-approved for treatment of insomnia) or placebo will be administered prior to going to bed following the evening WNE. This proposed study is the first to investigate the contribution of the orexin system to therapeutic effects of exposure-based treatment for PTSD through sleep. In the animal study, orexin neurons in the hypothalamus will be inhibited using optogenetic methods following a fear extinction training. For the career development plan, the candidate will participate in didactic and in-lab training activities in neuroscience and advanced research methodologies of both clinical and animal studies. The new skill set to be acquired during the K01 period will complement the candidate?s current expertise and enable her to develop an independent translational research program that strategically utilizes clinical and animal study methods to elucidate mechanisms underlying sleep?s contribution to resilience and PTSD recovery.